Certain derivatives of beta-aminopropiophenones



3,322,758 Patented May 30, 1967 The present invention relates to novel araliphatic amines of the following formula Y=a phenyl radical or a condensed multi-ring aromatic radical, one or more rings of which can the partially or completely saturated, such as, for example, phenyl, naphthyl, tetrahydronaphthyl, fluorene, anthracene or phenanthrene,

wherein Alk is a straight or branch chained alkylene group of l to 6 carbon atoms, Alk is a straight or branch chained trivalent radical of the formula C H wherein n is an integer from 2 to 6 and each of R and R is hydrogen, lower alkenyl or lower alkyl which can be joined together with each other or with Alk to a 5, 6 or 7 rnembered ring and such ring, if desired, can contain a further heteroatom, preferably, oxygen or sulfur, or the group NH The ring furthermore may be substituted by lower alkyl lower alkanoic acyl, benzyl, h-ydroxy lower alkyl, lower alkanoic acyloxy lower alkyl, carboxy ester and carbonyl amide groups,

R R =hydrogen, hydroxy, methoxy, nitro or chlorine,

R and R =H, CH O, NO or Cl,

R =hydrogen, methyl or ethyl,

R and R each=hydrogen or methyl and R =hydrogen or hydroxy and their pharmaceutically acceptable acid addition salts appearing at the right end of such structural formula will be designated as -Ph The compounds according to the invention can, for example, be produced by reacting a compound of the formula Ph O OCHz with a compound of the formula HNR -OH-GH-Ph R R6 together with formaldehyde or a formaldehyde yielding substance. Preferably such reaction is carried out at raised temperatures in the presence of a solvent.

It also is possible to react a compound of the formula Ph XGH-OH2Hal 1'1. wherein Hal is a halogen atom, preferably, chlorine or bromine, with a compound of the formula HNR -CHCHPh R11 R6 Preferably, such reaction is carried out at raised temperatures in the presence of a solvent and a basically reacting substance such .as alkali metal alcoholate, sodium amide, potassium carbonate, a tertiary amine or the like.

Similarly the compounds can also be prepared by reacting a compound of the formula Ph -XCHOHNR H with a compound of the formula Hal-G]E[CLE[P11 In the event the compound produced is one wherein -X is CO- it is possible to convert such compound or its salts into a compound wherein -X is CH(OH) by catalytic hydrogenation, that is, treatment with hydrogen in the presence of a catalyst, or other reductions known per se using, for example, sodium or lithium borohydride, alkali metal alcoholates, alkaline earth metal alcoholates or aluminum alcoholates as the reducing agents.

In addition, compounds according to the invention wherein X=CO can be prepared by reacting a compound of the formula Ph Me, wherein Me is a lithium, sodium or potassium atom, or a compound of the formula Ph MgHal with a compound of the formula wherein Hal is a halogen atom, preferably, chlorine or bromine.

Compounds according to the invention also can be prepared by reacting a compound of the formula Ph MgHal with a compound of the formula In the presence of water the amino ketones according to the invention are produced.

It also is possible to produce the compounds according to the invention by reductive condensation of a compound of the formula with a compound of the formula The bases which are produced which contain optically active carbon atoms and as a rule occur as r-acemates can be reacted with an optically active acid and be resolved into the optically active isomers by fractional precipitation or crystallization.

Furthermore, the novel bases according to the invention can be converted to their acid addition salts with acids having pharmaceutically acceptable anions such as I-ICl, H 80 H PO citric acid, lactic acid, succinic acid, maleic acid and the like and also to the quaternary ammonium compounds with pharmaceutically acceptable quaternizing agents.

The following examples will serve to illustrate the invention with reference to a number of specific embodiments thereof.

The radical Z in the formulae given in the examples signifies the radical CH3 OH EXAMPLE 1 1-N [3-phenyl-3-hydroxypropyl- (2 -;3-amin'0-3- 2- hydroxy-ethoxy -prpi0p'hen0ne.HCl

HO OHz C H2 15.1 g. of l-norephedrine were dissolved in 100 cc. of isopropanol and 18 cc. of isopropanolic HCl added thereto to provide a weak acidic reaction. Then 3.6 g. of paraformaldehyde and 18 g. of 3-(2-hydroxy-ethoxy)- acetophenone were added and the mixture boiled under reflux for 5 hours. The end product separated out from the reaction mixture upon cooling as white crystals. The melting point .after recrystallization from isopropanol was 139-l42 C.

Analogously the following compounds were prepared using paraformaldehyde, 1-norephedrine and the acetophenone indicated as starting materials.

(a) 1 [3 (2 dihydroxy propoxy) phenyl] {2- [3 phenyl 3 hydroxy propyl (2) amino] ethyl}- ketone.HCl

using: 3-(2,3-dihydroxy-propoxy)-acetophenone. Its melting point after recrystallization from methanol was 150- 153 C.

(b) 1 N [3 phenyl 3 hydroxy propyl (2)]- 8 -amino 3 (2 dimethylamino ethoxy) propiophenone.2HCl

using: 3 (2 dimethylamino-ethoxy)-acetophenone. Its melting point after recrystallization from methanol was 186-188 C.

(c) 1 3 (2 diallylamino ethoxy) phenyl {2- [3 phenyl 3 hydroxy propyl (2) amino] ethyl}- ketone.2HCl

using: 3-(Z-diallyl-amino-ethoxy)-a-cetophenone. Its melting point after recrystallization from ethanol was 183 C.

(d) 1 N [3 phenyl 3 hydroxy propyl (2)]- 4 B amino 3 (3 dimethylamino propoxy) propiophenone.2HCl

(CI-Is)z-NCHzCH2CHz0 using: 3-(3-dimcthylamino-propoxy) -acetophenone. Its melting point after recrystallization from methanol was 202204 C.

(e) 1 N [3 phenyl 3 hydroxy propyl (2)]- [3 amino 3 (1 dimethylamino isopropoxy) propiophenone.2HCl

using: 3-(l-dimethylamino-isopropoxy)-acetophenonc. Its melting point after recrystallization from ethanol was 162164 C.

(f) 1 N [3 phenyl 3 hydroxy propyl (2)]- 5 amino 2 (3 diethylamino propoxy) propiophenone.2HCl

using: 2 (3 diethylamino-propoxy)-acetophenone. Its melting point after recrystallization from ethanol was 194-196" C.

(g) 1 N [3 phenyl 3 hydrox-y propyl (2)]- p amino 3 (3 piperidino propoxy) propiophenone.2HCl

O-(CHrh-N H using: 3-(3-piperidino-propoxy)-acetophenone. Its melting point after recrystallization from methanol was 211- 213 C.

(h) 1 N [3 phenyl 3 hydroxy propyl (2)] l8 amino 3 (Z-morpholino ethoxy) propiophe- O-CHa Z.2IICl using: 3 methoxy-S-(3-dimethylamino propoxy)acetophenone. Its melting point after recrystallization from ethanol was 183185 C.

(i) 1- N [3 phenyl 3 hydroxy propyl-(2)1- 13- amino 3 methoxy 4 (2 dimethylamino ethoxy)- propiophenoneZHCl using: 3 methoxy 4 (2 dimethylamino ethoxy) acetophenone. Its melting point after recrystallization from methanol was ZOO-202 C.

EXAMPLE 2 14.5 g. (0.047 mol) of 1-acety1-4-(3-dimethylaminopropoxy) naphthalene.I-IC1, 8.7 g. (0.47 mol) of l-norephedrineHCl and 2.5 g. (0.083 mol) of paraformaldehyde in 100 cc. of isopropanol to which 5 drops of conc. HCl had been added were boiled under reflux on a Water bath for 2 hours. After 1 hours boiling a further 3 g. (0.1 mol) of paraformaldehyde were added. The solution was then cooled and 100 cc. of acetone added and then allowed to stand for 1 day. The dihydrochloride which precipitated out was recrystallized from methanol. Its melting point after such recrystallization was 202- 205 C.

We claim:

1. A compound selected from the group consisting of l-N 3-phenyl-3-hydroXypropyl-( 2) ]-;3-amino-3-(2- hydroXy-ethoxy)-propiopi1enone hydrochloride,

1- 3 (2-dihydroXy-propoxy -phenyl] -{2- 3-pheny1-3- hydroxy-propyl- 2) -amino] -ethyl}-ketone hydrochloride,

l-N-[3-phenyl-3-hydroxy-propy1-( 2) ]-/3-amino-3- (2- dimethylamino-ethoxy)-propiophenone dihydrochloride,

1-3-(Z-diallylamino-ethoxy)-phenyl-{2-[3-pheny1-3 hydroxy-propyl- 2 -amino] -ethyl}-ketone dihydrochloride,

l-N- 3-phenyl-3-hydroxy-propyl- (2) ]-fl-amino-3- 3- dimethyl-amino-propoxy)-propiophenone di'hydrochloride,

l-N- 3-phenyl-3-hydroxy-propyl- 2) ]-p-amino-3-( 1- dimethylamino-isopropoxy)-propiophenone dihydrochloride,

1-N- 3-phenyl-3 -hydroxy-p1"-opyl- 2) ]-B-amino-2- 3- diethylarnino-propoxy) -propi0phenone dihydroehloride,

1-N-[3-pheny1-3 -hydroxy-propyl- (2) -p-amino-3-( 3- piperidino-propoxy)-propiophenone dihydrochloride,

1-N- 3-phenyl-3-hydroXy-propyl- 2) ]-,8-amino-3- 2- morpholino-ethoxy)-propiophenone di hydrochloride,

l-N- 3-pheny'l-3-hydroxypropyl- 2) ]-fl-amino-3- methoxy-S-(3-dimethylamino-pr0poxy)-propiophenone dihydrochloride,

6 1-N-[3-phenyl-3-hydroxy-propyl-(2) ]-[3-amino-3- =methoxy-4- Z-dimethylamino-ethoxy) -propi-ophenone dihydrochloride, and 2- 3-phenyl-3-hydroxy-propyl- 2 -amino] -ethyl}-{ 4- [3 diniethylamino-propoxy]-naphthyl-(1)}-ketone dihydrochloride and the corresponding free base.

2. A compound selected from the group consisting of l-N[3-phenyl-3-hydroXy-propyl-(2) J-fi-amino-B-(Z- hydroxy-ethoxy) -propiophenone hydrochloride and the corresponding free base.

3. A compound selected from the group consisting of 1-[3-(Z-dihydroxy-propoxy)-phenyl]-{2-[3-phenyl-3- hydroxy-propyl- 2 -arnino] -ethyl} -ketone hydrochloride and the corresponding free "base.

4. A compound selected from the group consisting of 1-N-[3-phenyl-3-hydroxy-propyl-(2) -/S'-amino-3-( 2- dimethylamino-ethoxy) -propi0phenone dihydrochloride and the corresponding free base.

5. A compound selected from the group consisting of 1-N-[3-phenyl-3-hydroXy-propyl-(2) ]-fi-amino-3-(3- dimethylamin-o-propoxy)-propiophenone dihydrochloride and the corresponding free base.

6. A compound selected from the group consisting of 1-N- 3-phenyl-3 hydroXy-propyl- 2 -fi-amino-3 3 piperidino-propoxy)-propiophenone dihydrochloride and the corresponding free base.

7. A compound selected from the group consisting of 1-N- 3-phenyl-3-hydroxy-propyl- 2) ]-,B-amino-3- 2- morpholino-ethoxy)-propiophenone dihydrochloride and the corresponding free base.

8. A compound selected from the group consisting of {2-[3-phenyl-3-hydroXy-propyl-(2)-a-mino]ethyl}-{4-[3- dimethylamino-propoxy]-naphthyl-(1)}-ketone dihydrochloride and the corresponding free base.

References Cited UNITED STATES PATENTS 2,619,485 11/1952 Cha brier et al 260-247.5 3,185,691 5/1965 Pribyl et a1 167- 3,193,579 7/1965 Goldberg et a1. 167-65 3,225,095 12/1965 Thiele 260570.6

FOREIGN PATENTS 921,940 1/ 1955 Germany.

ALEX MAZEL, Primary Examiner. HENRY R. JILES, Examiner.

RICHARD J. GALLAGHER, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 1-N(3-PHENYL-3-HYDROXYPROPYL-(2))-B-AMINO-3-(2HYDROXY-ETHOXY)-PROPIOPHENONE HYDROCHLORIDE, 1-(3-(2-DIHYDROXY-PROPOXY)-PHENYL)-(2-(3-PHENYL-3HYDROXY-PROPYL-(2)-AMINO) -ETHYL)-KETONE HYDROCHOLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPLY-(2))-B-AMINO-3-(2DIMETHYLAMINO-ETHOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-3-(2-DIALLYLAMINO-ETHOXY)-PHENYL-(2-(3-PHENYL-3HYDROXY-PROPYL-(2)-AMINO) -ETHYL)-KETONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPYL-(2))-B-AMINO-3-(3DIMETHYLAMINO-PROPOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPLY-(2))-B-AMINO-3-(1DIMETHYLAMINO-ISPROPOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPYL-(2))-B-AMINO-2-(3DIETHYLAMINO-PROPOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPYL-(2)-B-AMINO-3-(OPIPERIDINO-PROPOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXY-PROPYL-(2)--B-AMINO-3-(2MORPHOLINO-ETHOXY) -PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-PHENYL-3-HYDROXPROPYL-(2))-B-AMINO-3METHOXY-5-(3-DIMETHYLAMINO -PROPOXY)-PROPIOPHENONE DIHYDROCHLORIDE, 1-N-(3-HYDROXY-PROPYL-(2))-B-AMINO-3METHOXY-4-(2-DIMETHYLAMINO-ETHOXY) -PROPIOPHENONE DIHYDROCHLORIDE, AND (2-(3-PHENYL-3-HYDROXY-PROPYL-(2)-AMINO)-ETHYL)-4-(3DIMETHYLAMINO-PROPOXY) -NAPHTHYL-(1)-KETONE DIHYDROCHLORIDE AND THE CORRESPONDING FREE BASE. 